C O M M U N I C A T I O N S
protecting arrangement to afford 13. The hydroxymethyl lactam
was converted to the imidate ester 4 as shown by a sequence
consisting of Jones’ oxidation, esterification, and treatment with
Meerwein reagent (Et3OBF4). With the lactam functionality thus
masked, treatment of 4 with LHMDS led to exclusive anion
formation at C4. Internal acylation with the pendant ethyl carbonate
proceeded smoothly to afford lactone 14.4 Acidic treatment of 14
led to the restoration of the lactam moiety, which was subsequently
protected with PMBCl. Removal of the benzyl protecting group
afforded 15.
Upon conversion of the benzyl ester to an aldehyde, intermediate
7 was in hand.
Treatment of 7 with the cyclohexenyl zinc reagent, 8, under the
Corey protocol3 proceeded with excellent diastereocontrol to afford
19 in 88% yield (dr ) 20:1 at C6). By sharp contrast, the use of
the corresponding imidate aldehyde derived from 1412 instead of 7
resulted in poor diastereoselectivity (78% yield, 4:3, configuration
not determined). Obviously, the PMB group plays a critical role in
diastereoselection in the novel Corey reaction.3
Removal of the PMB group from 19, followed by reductive
opening of the benzyl glycoside, gave rise to triol 20. Acidic
cleavage of the tert-butyl ester was effected through treatment with
BCl3, and the crude trihydroxy acid was then subjected to
lactonization-chlorination3 to provide 1, whose spectroscopic
properties were in complete accord with the natural material.1 In
addition, the structure of fully synthetic 1 was corroborated
crystallographically.
The lactone of 15 was subjected to nucleophilic ring opening
with phenylselenium anion,8 and the resultant carboxylic acid was
benzylated to afford the differentially esterified 16 (Scheme 3).
Scheme 3. Synthesis of Salinosporamide Aa
In summary, an efficient and highly stereocontrolled enantiose-
lective synthesis of salinosporamide A has been achieved. Several
key features of our synthesis include the temporary masking of a
lactam functionality to accomplish selective anion formation at C4
(see 4), the use of a nucleophilic selenium species to open a lactone
in a regiocontrolled fashion (see 15), and the use of an unusual
cationic hemiacetal selenocyclization to install the quaternary center
at C3 in manageable form with complete stereocontrol.
Acknowledgment. This work was supported by the National
Institutes of Health (S.J.D. CA28824). A postdoctoral fellowship
is gratefully acknowledged by A.E. (Mr. William H. Goodwin and
Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer
Research, the Experimental Therapeutics Center, SKI). We also
thank Dr. Louis Todaro (Hunter College, The City University of
New York) for X-ray structural analyses and Dr. George Sukenick
(NMR Core Facility, SKI) for mass spectral analyses.
a Key: (a) PhSeSePh, NaBH4, EtOH, 60 °C; (b) BnBr, K2CO3, DMF, rt
(65% in 2 steps); (c) 30% H2O2 aq, THF, rt; (d) toluene, 100 °C (94% in
two steps, 72% 17 + 22% 5); (e) Dess-Martin periodinane, CH2Cl2, rt
(92%, 89% in three steps from 16); (f) PhSeBr, AgBF4, BnOH, CH2Cl2,
-20 to 0 °C (74% as an anomeric mixture, 12:1); (g) AIBN, n-Bu3SnH,
toluene, 100 °C (98%); (h) NaBH4, THF-EtOH (3:1), rt (85%); (i) Dess-
Martin periodinane, CH2Cl2, rt (95%); (j) 8, THF, -78 °C (88% for 19, dr
) 20:1); (k) ceric ammonium nitrate (CAN), CH3CN-H2O, 0 °C (90%);
(l) Na, liq NH3, -78 °C; (m) NaBH4, THF-H2O (2:1), rt (97% in two
steps); (n) BCl3, CH2Cl2, 0 °C; (o) BOPCl, TEA, CH2Cl2, rt; (p) Ph3PCl2,
pyridine, CH3CN, rt (51% in three steps).
Supporting Information Available: Experimental procedures and
characterization, including polarimetric data, for new compounds. In
addition, confirmatory crystallographic data for 1 and 19 are included.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Surprisingly, the subsequent selenide oxidation elimination sequence
gave rise to a mixture of the expected alcohol 17 (72%), along
with aldehyde 5 (22%), which was in fact a one-step advancement
in our planned synthetic route. Upon purification, we converted
the bulk unoxidized material, 17, to aldehyde 5 through exposure
to Dess-Martin periodinane.9
References
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With intermediate 5 in hand, the stage was now set for a key
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(12) See Supporting Information for method of synthesis.
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